Khatami et al. BMC Medical Genetics(2020) 21:226
https://doi.org/10.1186/s12881-020-01168-x

RESEARCH ARTICLE

Open Access

Novel MYO15A variants are associated withhearing loss in the two Iranian pedigrees
Somayeh Khatami1, Masomeh Askari2, Fatemeh Bahreini3, Morteza Hashemzadeh-Chaleshtori4,
Saeed Hematian4 and Samira Asgharzade4*

Abstract
Background: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard toits high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations
using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus
developed in this domain to remove the limitations of conventional methods.
Methods: This study was a report on a research study of two unrelated pedigrees with multiple affected cases ofhearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families.
Results: The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) diseasecausing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:
p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations andsegregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects.
Conclusion: In this study, whole exome sequencing were used as a first approach strategy to identify the two novel
variants in MYO15A in two Iranian families with ARNSHL.
Keywords: MYO15A, Whole exome sequencing, First approach, Consanguineous

Background
Hearing impairment is considered as an etiologically heterogeneous sensory deficiency with incidence 1 in 1000
newborns around the world [1]. In this regard, genetic
hearing loss (HL) has been divided into syndromic andnon-syndromic types. Considering the high rate of consanguineous marriages in the Middle East, autosomal recessive
non-syndromic hearing loss (ARNSHL) is reportedly moreprevalent western countries [2]. However; due to the wide
variety of pathogenic genes associated with nonsyndromic hearing loss (NSHL), including both nuclear
and mitochondrial ones, the disease includes diverse
patterns of inheritance comprised of autosomal* Correspondence: Asgharzade2336@gmail.com
4
Cellular and Molecular Research Center, Basic Health Sciences Institute,
Shahrekord University of Medical Sciences, Shahrekord, Iran
Full list of author information is available at the end of the article

dominant, autosomal recessive, mitochondrial, and Xlinked recessive. Disease heterogeneity has been admittedly recognized as the most important challenge in
genetic diagnosis of NSHL. Diagnostic approaches
which have been relied on conventional methods basedon genetic testing of the most common genes, often failto determine the exact genetic cause of the disease inmany countries including Iran [3]. In heterogeneous
populations like Iran, the distribution of mutations in
the gap junction beta-2 protein, also known as connexin 26, (i.e. GJB2) gene as a major cause of ARNSHL
can be extremely diverse depending on patients’ ethnicities. The prevalence rate of GJB2-related hearing loss
has been reported by 38.3% in northern Iran, but thepercentage of such variations has been found very
rarely in southern regions [3]. Various frequencies of
causative mutations, compound heterozygotes, as well

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Khatami et al. BMC Medical Genetics(2020) 21:226

as nuclear modifier genes can also render the moleculardiagnosis of ARNSHL as a challenge [3, 4]. Moreover, mutation screening in large genes such as MYO15A (66exons) can be impeded following the use of traditional approaches based on Sanger sequencing [5, 6]. Today, molecular genetic testing on the basis of multi-genescreening such as whole-exome sequencing (WES) are being used instead of traditional diagnostic procedures [7].
For first time, MYO15A (DFNB3 locus) mutation wasreported from Indonesia population. Until now, there havebeen many reports of mutations of MYO15A causing
ARNSHL in different countries of Asia such as Pakistan[8], Turkey [9] and Iran [6]. In the present study, twonovel MYO15A variants identified by WES from two Iranian families with ARNSHL is reported.

Methods
Subjects and clinical evaluations

The study was approved by the Ethics Committee of Shahrekord University of Medical Sciences (IR.SKUMS.REC.1397.008), Iran. Two Iranian families from Hamedan
Province with hearing impairments, without any other additional symptoms were thus studied. Informed written consent was taken from both families. The proband from eachfamily was further subjected to clinical evaluations of theinner ear accompanied by pure-tone audiometry (PTA).
Molecular analysis

WES was used to detect the deafness associated variantsin the DNA sample in probands. Genomic deoxyribonucleic acid (DNA) was extracted from whole peripheral
blood of each study subject utilizing DNA Extraction Kit
DNP (Sinacolon, Iran) according to the manufacturer’s
instructions. Purity and concentration of DNA samples
were further measured via Thermo Scientific NanoDrop
2000c Spectrophotometer.
DNA samples from each pedigree’s proband (Fig. 1a,
V-4 in family 1; Fig. 1c, II-3 in family 2) were then subjected to WES at Macrogen Online Sequencing Order
System (Seoul, South Korea) on Genome Analyzer/
HiSeq 2000 (Illumina, San Diego, CA, USA, 151-bp
paired-end reads). It should be noted that the library
had been prepared through SureSelect XT Library Prep
Kit (Agilent Technologies, CA, USA). Data analysis wascorrespondingly performed using an in-house developed
pipeline, adopted from Genome Analysis Tool Kit v3.6
and ANNOVAR software [10]. Homozygous missense,
start codon change, splice site, nonsense, stop loss, andindel variants with minor allele frequency < 1% were further filtered in dbSNP (version 138), 1000 Genomes Project, Exome Aggregation Consortium (ExAC), andNHLBI GO Exome Sequencing Project (ESP). Based on
autosomal recessive inheritance, the homozygosity

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region of samples was determined using homozygosity
mapping algorithms.
In order to prioritize the candidate functional variants,
several online prediction software including MutationTaster2, FATHMM, PANTHER, SIFT, PROVEAN,
MetaLR, PolyPhen-2, CADD, and ConSurf were also
used to evaluate the pathogenic effects of the variants
with a frequency less than 0.01. After observing theautosomal recessive inheritance pattern in both pedigrees, the homozygous variants were then prioritized.
Next, the variants were investigated in the Human Gene
Mutation Database, hereditaryhearingloss home page
and the related literature to survey their association witha phenotype and novelty of the variants.
Besides, candidate variant segregation from exome data wasevaluated through polymerase chain reaction (PCR)-based
Sanger sequencing. Therefore, the following primers were synthesized: 5 -GAACTACATCGTGCAGAAGG-3 and 5 CCTATCCAGTCCCACTCACT-3 for human MYO15A c.
T6442A variant and 5 -CCACCATTCGGCCTTCCA-3
and 5 -CTGCCTCCTCTTAGTGTCCTC-3
for human
MYO15A c.10504dupT variant.

Results
Clinical and molecular findings
Family1

The first family pedigree is displayed in Fig. 1a. Accordingly, four members of the pedigree including two affected and two unaffected individuals who consented to
be included in this study are indicated. In this family,
the proband (V: 4) was a 21-year-old woman with congenital HL. No additional abnormal phenotypic features
including visual impairments or any limb and facial malformations were observed in the proband. The parents
were consanguineous and both showed normal hearing.
According to the audiogram, the proband is sufferingfrom congenital profound deafness (Fig. 1b).
Family2A three-generation pedigree, depicted in Fig. 1c, was presented as the second family with ten members, six males
and fourteen females, suffering from ARNSHL. The proband was a 25-year-old male individual, born as the second child of non-sanguineous healthy parents, who had
been diagnosed for congenital HL when he was 1 year old.
At the age of 5, he had gone through bilateral cochlear implant surgery based on physical examinations and audiometry testing. Audiogram analysis also confirmed HL to be
profound in the proband (II: 3) (Fig. 1d).
Considering the all limitations in genetic diagnosis of
ARNSHL, it was decided to perform WES as a first approach on proband’s genome DNA. The total number ofbases, reads, GC (%), and Q30 (%) are calculated for the
subjected sample. 70,760,838 reads were produced, andKhatami et al. BMC Medical Genetics(2020) 21:226

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Fig. 1 Pedigrees and the proband audiograms, as well as sequencing chromatograms. a Pedigree of family 1 having autosomal recessive form of
NSHL disease is drawn. The proband (V: 4), for whom whole exome Sequencing has been carried out is indicated by arrow. b Audiogram for puretone audiometry (PTA) of the proband (V: 4) with profound hearing loss in both ears. c Three-generation pedigree of family 2 having autosomal
recessive form of NSHL disease is drawn. The proband (II: 3), for whom whole exome Sequencing has been carried out is indicated by arrow . d
Audiogram for pure tone audiometry (PTA) of left and right ears of the affected proband (II: 3) showed profound hearing loss. Hearing impaired
individuals are illustrated by black-filled symbols. e Partial sequence chromatograms of MYO15A gene from two unaffected (IV.2 and V.5) and affectedindividuals (V: 3 and V: 4) in family 1 illustrate T to A transition at position 6442. f Partial sequence chromatograms of MYO15A gene containing(c.10504dupT:p.C3502Lfs*15) variant in proband (II: 3), his father (I: 1) and his siblings (II: 2 and II:5) in family 2 illustrates insertion of T as indicatedtotal read bases were 10.7G bp. The GC content (%) andQ30 were 51.87 and 95.69% respectively. Following the filtering step depicted in Fig. 2, two novel homozygous variants in MYO15A i.e. c.T6442A:p.W2148R and c.10504
dupT:p.C3502Lfs*15 were prioritized in family I and II,

respectively. Given that the proband of family I was the offspring of consanguineous parents, WES dataset revealed
that MYO15A (c.T6442A) variants had resided in the large
homozygous regions on chromosome 17 (Fig. 3). All insilico programs also predicted damaging effects ofKhatami et al. BMC Medical Genetics(2020) 21:226

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Fig. 2 Schematic flow chart of the filtering of causative variants in this study

p.W2148R variant. Mutation taster further suggested thatc.10504dupT variant had deleterious effects. Moreover, thefirst conservative amino acid alternation (p.C3502L) predicted to be pathogenic using online softwares (Table 1).
Analysis of genotype-phenotype correlations revealed thatpatients with c.T6442A:p.W2148R and c.10504dupT:
p.C3502Lfs*15 tended to have profound hearing loss.
Additionally, the results of Sanger sequencing confirmed
the presence of p.W2148R variant in MYO15A gene in theproband and other affected members who were studied,but the unaffected sister (V.5) and her father were foundheterozygous for the variant (Fig. 1e).
The findings of Sanger sequencing also revealed cosegregation of c.10504dupT variant in the second family(Fig. 1f). The affected proband was thus homozygous,
whereas his unaffected sister (II:5) and his father (I:1)
were heterozygous for this locus and his unaffectedbrother (II:2) lacked the variant.
It should be noted that these two variants were absent
in 50 ethnically-matched control cases.

Fig. 3 Homozygosity region in the proband (V: 4) of pedigreeI. Coordinate homozygosity region on chromosome 17 inproband [17927849–18,239,689]

Khatami et al. BMC Medical Genetics(2020) 21:226

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Table 1 In Silico and Bioinformatics Analysis of the Variants
Variant

c.T6442A:p.W2148R

c.10504dupT:p.C3502Lfs*15

Locus

DFNB3

DFNB3

dbSNP rsID

Novel

Novel

ConSurf score

8

8

MutationTaster2

Disease causing

Disease causing

SIFT

Damaging

deleterious

Polyphen2

Probably damaging

Probably damaging

FATHMM

Damaging

Damaging

PROVEAN

Deleterious

Deleterious

MetaLR

Damaging

Not down

CADD_phred24.3

Not down

PANTHER

Probably damaging

Probably damaging

Segregates in the family

Yes

Yes

*Creating a new reading frame ending at a stop codon at position 15

Discussion
Based on WES data as well as segregation and genotypephenotype correlational studies, mutations in MYO15A
gene were identified as a main contributor of NSHL in
the first and second surveyed families.
MYO15A, as a new branch of the myosin proteincoding gene superfamily, has a role in stereocilia formation [11]. This gene is considered as the third leading
cause of ARNSHL in many populations [12, 13], including Iran, with a prevalence rate ranged from 4.8–9.6%[14–16] . Moreover, mutations in this gene have been
associated with severe-to-profound HL. Screening of 66
coding exons through Sanger sequencing is expensive
and more time-consuming. On the contrary, highthroughput techniques can save time and money [17].
MYO15A is a different form of myosins protein withlong N-terminal extensions following by the conserved
motor domain, IQ motifs (calmodulin/ myosin lightchain binding), MyTh4 domains (Myosin-Tail like Homology region 4), FERM motifs (4.1 protein, Ezrin,
Radixin, and Moesin), SH3 domain (Src Homology 3),
and the PDZ ligand domain (Post synaptic density protein (PSD95), Dlg1 (Drosophila disc large tumor suppressor), and zo-1 (Zonula occludens-1 protein) [18].
The identified c.T6442A: p.W2148R variant in our study
is located in the first (MyTH4) domain and is also conserved among different species (data not shown). The association of (MyTH4) domain mutations with hearing
loss was firstly reported in 1998 [19]. Due to documents,
variants in this domain have related severe to profoundhearing loss, which is consistent with our pedigree
phenotype [5, 15, 16, 20–22]. To the best of our knowledge, p.P2073S, p.R2124Q [22] p.P2073L, p.V2114G[16], R2146Q [23], p.R2146W [24] and c.6273 + 1G > A[25] variants have been detected in Iranian population
until now [15, 16, 22]. The p.R2124Q and p.P2073S were

the first reported mutations in the MyTH4 domain of
MYO15A protein which was located in conserved fourth
helix of MyTH4. Variations in the MyTH4 domains
interfere in forming of transmembrane actin microfilament assembly complex at the stereocilia tips [22].
Mehregan et al., reported p.Arg2146Gln in the fourth
helix of the first MyTH4 core, which results in severe toprofound hearing loss. Structural analysis of this variation has revealed that this substitution alters binding
properties at the domain surface [24].
The substitution of a highly conserved amino acid
(Table 1), hydrophobic non-polar tryptophan, with arginine can lead to a loss of hydrophobic pocket. The counterparts of p.W2148 in the more studied family members, i.e.
MYO7A is W1192. Sans CEN2 (a scaffold protein) interacted with MyTH4 domain by extensive hydrogen bonding, hydrophobic contacts, and charge-charge interactions.
The hydrophobic pocket in MYO7A comprised the conserved A1189, W1192, I1193, P1220, and Y1223 residues.
Substitution of Ala1189 by Glu, leads to a.
~ 10-fold decrease of the binding affinity between
MyTH4 domain and CEN. The complex of myosins andSANS linked cadherins to the actin cytoskeleton [26]. Woo
et al., explained that p.R2146Q in myosin 15A and
R1190 of MYO7A had similar structure in MyTH4FERM domains and interfere to binding CEN2 to thisdomain [5].
In addition, Myosin interacts with other scaffolding proteins (whirlin and Eps8 (Epidermal Growth Factor Receptor Pathway Substrate 8)) and can transport them to thetip of stereocilia to form a stereocilia tip complex, which
can facilitate maturation of stereocilia. These scaffold proteins are essential for normal hearing in humans [27, 28].
MyTH4 domain contains the actin-binding sites. The
overall surface of the microtubule (MT) is negatively
charged. The positively charged motifs with surface-Khatami et al. BMC Medical Genetics(2020) 21:226

exposed hydrophobic side chains found in the myosin
MyTH4 domain can serve as an MT binding site [29].
We speculate the, c.T6442A:p.W2148R variant interferes with the formation of the Myosin 15A-whirlinEps8-CEN2 complexs and microtubule-binding.
In the second studied family, WES could successfully detect a novel homozygous insertion variant i.e. c.10504dupT:
p.C3502Lfs*15 in MYO15A gene, co-segregated with thedisease within the pedigree. This variant between thesecond FERM and PDZ domains could also lead to a reading frame shift at position 10,504 and a stop codon(p.C3502Lfs*15) with truncation and translation of mRNA
resulting in lack of its conserved amino acids at C-terminal(data not shown). Lezirovitz et al. reported a frameshift mutation c.10573delA to cause profound.
hearing loss. This mutation in the PDZ binding ligandof MYO15A altered interaction of this protein with whirlin. Thus, stereocilia elongation did not occurred [30].
Zhang et al. identified p.Leu3501Glu variant was associated with profound hearing loss [17].
Today, the topic of oligogenic inheritance traits has
made a big wave in diagnostic medicine; since, in many
monogenic diseases, it represents that there is not justone gene affected phenotype which causes new challenges in diagnosing these diseases and it can be more
complicated for diseases with heterogenic pathology inwhich many genes are involved [31].

Conclusion
In summary, we identified two novel variants (p.W2148R
and p.C3502Lfs*15), in the MYO15A gene in two Iranianfamilies using whole-exome sequencing. Accordingly, we
showed that these likely pathogenic variants were segregated with the profound hearing loss in both families.
However, further functional analysis is required to confirm the results of the present study.
Abbreviations
AR: Autosomal recessive; ExAC: Exome Aggregation Consortium; ESP: Exome
Sequencing Project; ESP8: Epidermal Growth Factor Receptor Pathway
Substrate 8; FERM: 4.1 protein, Ezrin, Radixin, and Moesin; MyTh4: Myosin-Taillike Homology region 4; NSHL: Non-syndromic hearing loss; PTA: Pure-toneaudiometry; SH3: Src Homology 3; WES: Whole exome sequencing; zo1: Zonula occludens-1 protein
Acknowledgements
We sincerely thank the patients and their families for participating in thisstudy.
Authors’ contributions
SK, data analysis, wrote the manuscript, answered Reviewers comments,
proved manuscript final version; MA, data analysis, performed experiments,
technical editing and revising the manuscript; FB, performed experiments,
technical editing and revising the manuscript; MHC, prepared reagents/tools,
technical editing and revising the manuscript, proved manuscript final
version; SH, planned and performed experiments, proved manuscript final
version, SA, study design, validated data, wrote the manuscript, proved
manuscript final version. The author(s) read and approved the final
manuscrip.

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Funding
This work was financially supported by Sharekord University of Medical
Sciences. Whole exome sequencing and its data collection and data analysis
were supported by Sharekord University of Medical Sciences (grant No.
2685).
Availability of data and materials
The raw datasets generated and/or analyzed during the current study are
not publicly available because it is possible that individual privacy could becompromised, but are available from the corresponding author on
reasonable request.
Ethics approval and consent to participate
The study was approved by the Review Board of Sharekord University of
Medical Sciences (IR.SKUMS.REC.1397.008). Written informed consent was
obtained from all of the participants in the study and a written consent toparticipate was obtained from the parents of the patient (younger than theage of 16).
Consent for publication
Written informed consent for publication of clinical details and clinicalimages was obtained from the all of the participants. The parents /legal
guardian of the children (under the age of 18) has signed written informed
consent for publication of clinical and genetic data.
Competing interests
All authors declare no conflict of interest.
Author details
1
Department of Genetics and Molecular Medicine, School of Medicine,
Zanjan University of Medical Sciences, Zanjan, Iran. 2Department of Genetics
at Reproductive Biomedicine Research Center, Royan Institute for
Reproductive Biomedicine, ACECR, Tehran, Iran. 3Department of Molecular
Medicine and Genetics, Faculty of Medicine, Hamadan University of Medical,
Hamadan, Iran. 4Cellular and Molecular Research Center, Basic Health
Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord,
Iran.
Received: 1 December 2019 Accepted: 10 November 2020

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